tbuckley/cabot-search huggingface dataset:
TRIDENTE trial: A phase II study of rechallenge with encorafenib, binimetinib, and cetuximab in patients with RAS wild-type/BRAF V600E–mutant metastatic colorectal cancer.
Authors: Daisuke Kotani, Yoshinori Kagawa, Yuki Matsubara, Hideaki Bando, Kazuaki Harada, Naoki Takahashi, Yoshiaki Mihara, Izuma Nakayama, Naoki Izawa, Takeshi Kawakami, Toshiki Masuishi, Hiroko Hasegawa, Takashi Ohta, Masashi Wakabayashi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2023)

TPS264 Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m 2 , and subsequently 250 mg/m 2 , QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .
Trial in progress: A phase 2, multicenter, open-label study of DKN-01 in combination with tislelizumab and chemotherapy as 1L therapy in patients with unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ; DisTinGuish).
Authors: Keun-Wook Lee, Markus H. Moehler, David Cunningham, Zev A. Wainberg, Hope Elizabeth Uronis, Do-Youn Oh, In-Ho Kim, Byoung Yong Shim, Sun Jin Sym, Rachel A Altura, Melissa C Stilian, Elizabeth C Parker, Samuel J Klempner
Journal: Journal of Clinical Oncology (2023)

TPS484 Background: Advanced G/GEJ cancer is a major cause of cancer-related mortality requiring novel therapies. DKN-01 is a humanized mAb that binds and neutralizes DKK1. DKK1 plays a major role in WNT-pathway regulation and is overexpressed in multiple cancers. DKK1 expression is associated with poor prognosis, an immunosuppressive tumor microenvironment, and resistance to chemotherapy in G/GEJ cancer. The non-randomized Part A of DisTinGuish demonstrated durable clinical benefit in patients with G/GEJ adenocarcinoma. Higher response rates were observed in patients with high tumoral DKK1 expression, when DKN-01 was administered in combination with an anti-PD1 mAb, tislelizumab, and chemotherapy 1,2 . Furthermore, in Part B, durable responses were seen in 2L patients with DKK1-high G/GEJ cancers treated with a chemotherapy-free doublet regimen, DKN-01 plus tislelizumab 1 . Part C will evaluate the efficacy of this chemoimmunotherapy combination in a randomized fashion in treatment-naïve G/GEJ adenocarcinoma patients. Methods: Part C is an ongoing, global, randomized phase 2 open-label study evaluating DKN-01 in combination with tislelizumab + chemotherapy (CAPOX or mFOLFOX6) vs tislelizumab + chemotherapy in patients with advanced G/GEJ adenocarcinoma. Patients are randomized 1:1 and stratified by DKK1 and PD-L1 expression. Approximately 160 patients will be enrolled from 5 different countries. Key inclusion criteria include patients with HER2 negative, G/GEJ adenocarcinoma who have received no prior systemic treatment in the unresectable locally advanced/metastatic setting and can provide tumor tissue to document PD-L1 CPS and DKK1 expression, as performed at a central lab. Key exclusion criteria include prior treatment with anti-PD1/L1/L2. The primary endpoint is PFS according to RECIST v1.1 as assessed by the investigator in patients with DKK1-high tumors. Key secondary and exploratory end points include PFS, OS, ORR, DoR in patients with tumors with any level of DKK1 expression, as assessed by both investigator and by blinded, central review. Recruitment is ongoing. Clinical trial information: NCT04363801 . References SJ Klempner, et al. DKN-01 and tislelizumab ± chemotherapy as a first-line (1L) and second-line (2L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial. JCO 40, no. 4_suppl, 2022, 292-292.&amp;nbsp; SJ Klempner, et al. DKN-01 and Tislelizumab + Chemotherapy as First-line (1L) Investigational Therapy in Advanced Gastroesophageal Adenocarcinoma (GEA): DisTinGuish Trial. ESMO Annual Meeting September 2022. Clinical trial information: NCT04363801 .
Real-world registry of patients with unresectable hepatocellular carcinoma: The OREIOS study.
Authors: Stephen Lam Chan, Min-Hee Ryu, Imam Waked, Yu Yun Shao, Wai Meng David Tai, Valeriy Breder, Ashwaq Alolayan, Sandip Ganguly
Journal: Journal of Clinical Oncology (2023)

TPS618 Background: A majority of patients with hepatocellular carcinoma (HCC) are diagnosed with unresectable disease due to extensive extrahepatic spread, presence of multifocal tumors, poor hepatic function or tumor location near major intrahepatic vessels. The treatment landscape for unresectable HCC is rapidly evolving with availability of novel agents, mandating evidence-based therapeutic algorithm for optimum clinical outcomes. Integrating newly approved and emerging therapies in this extremely heterogeneous HCC population with coexisting risk factors (performance status, Child-Pugh class, macrovascular invasion or extrahepatic metastases, and alpha-fetoprotein levels) may pose challenge without understanding survival outcomes with the current treatment practices. Also, application of immunotherapy and targeted agents in clinical practice displays significant regional variations. Real-world evidence on the management of unresectable HCC is sparse across different geographies. The OREIOS study aims to describe the management patterns, clinical characteristics, possible predictors, and survival outcomes in patients with unresectable HCC in 12 countries across Asia, Latin America and the Middle East. The data may serve in devising policies on optimal patient selection and sequencing of novel systemic therapies for unresectable HCC. Methods: OREIOS is an ongoing multicenter, retrospective, non-interventional registry in adults diagnosed between 01 January 2017 and 31 December 2019 with unresectable BCLC stage B HCC, ineligible for initial loco-regional therapy or stage C advanced or metastatic disease, with at least 12 months (or until death if it occurs within 12 months of diagnosis) of available records. Patients with BCLC stage D and other concomitant metastatic cancers are excluded. Data collection includes socio-demographics, clinico-pathological characteristics, treatment modalities, survival outcomes, comorbidities and liver function status. Primary outcome measures include median overall survival using the Kaplan–Meier method and survival rates at 6, 12, 18 and 24 months. Secondary outcomes include clinico-demographic characteristics, treatment regimens (alone or combination) in each line of therapy and real-world progression-free survival. Additionally, prognostic and predictive factors for survival outcomes will be evaluated. Of the planned sample size of 1440 patients, a total of 473 patients with unresectable HCC have been enrolled until August 2022 across 7 countries (Egypt: 105, Hong Kong: 107, India: 79, Russia: 100, Saudi Arabia: 27, Singapore: 50, South Korea: 05). Data collection is currently ongoing and results are expected by 2024. Clinical trial information: NCT05239507 .
Perioperative penpulimab plus anlotinib combined with chemotherapy for locally advanced gastric cancer: A single arm, multicenter, phase II clinical trial.
Authors: Mian Wang, Wei Zhou, Yan Miao, Zhaobang Tan, Yiding Li, Liu Hong
Journal: Journal of Clinical Oncology (2023)

TPS485 Background: Perioperative therapy, especially whether preoperative neoadjuvant therapy (NAT) can improve R0 resection rate and prolong overall survival of patients with locally advanced gastric cancer, has been paid more and more attention. NAT is mainly defined as a preoperative chemotherapy or chemoradiotherapy, aiming at increasing radical resection rate by downstaging tumor and eliminating micrometastases. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4 and PDGFRα/β, which effectively blocks tumor neovascularization and growth. Previous phase I/II clinical trials suggested that penpulimab monotherapy as second-line therapy was well tolerated and showed clinical anti-tumor activity in gastric or gastroesophageal junction carcinoma (GC/GEJ) (NCT03352531, NCT04172506). It was demonstrated an objective response rate (ORR) of 26.3%, a disease control rate (DCR) of 42.1% in GC/GEJ patients (pts) using penpulimab monotherapy. This trial was designed to assess the feasibility and efficacy of penpulimab plus anlotinib combined with chemotherapy in perioperative treatment of pts with locally advanced gastric cancer. Methods: This is a multi-center, prospective, single-arm, phase II study. Resectable GC pts with TNM stage T3~4N+M0 per AJCC 8th , ECOG PS 0-1, were enrolled and treated with 3 cycles of preoperative penpulimab (200mg, iv, d1, q3w) + anlotinib (12mg, qd, d1-d14, q3w)+ SOX (oxaliplatin 130mg/m 2 , iv, d1 and S-1 40-60mg, po, bid, d1-14, q3w), and 12 months of postoperative adjuvant therapy formulated by investigators according to the individual situation of the pts. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included major pathologic response (MPR) rate, disease free survival (DFS), objective response rate (ORR), R0 resection rate and safety. Based on a two-sided test for one proportion with 5.0% type I error, 80% power to detect an improvement in the rate of pCR from 13% to 29%, there will be 57 pts enrolled considering 10% of pts dropping out. Clinical trial information: NCT05385900 .
Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).
Authors: Dustin A. Deming, Jordi Rodon Ahnert, Michael J. Demeure, Noah Federman, Meredith McKean, Elizabeth Katherine Lee, Alexander I. Spira, David J. Kwiatkowski, Maen A. Hussein, Erlinda Maria Gordon, David G. Crockett, Kristen N. Ganjoo, Brian Schulte, Lee D. Cranmer, Anita N. Schmid, Willis H. Navarro, Loretta Marie Itri, Gopa Iyer
Journal: Journal of Clinical Oncology (2023)

TPS818 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m 2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]
Pertuzumab plus trastuzumab (P+T) in patients (pts) with biliary tract cancer (BTC) with ERBB2/3 amplification (amp), overexpression (oe), or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Timothy Lewis Cannon, Michael Rothe, Elizabeth Garrett-Mayer, Vi Kien Chiu, Jimmy J. Hwang, Namrata Vijayvergia, Olatunji B. Alese, Elie G. Dib, Herbert Leon Duvivier, Kelsey Klute, Vaibhav Sahai, Eugene R Ahn, Deepti Behl, Sarah Sinclair, Ramya Thota, Walter John Urba, Eddy Shih-Hsin Yang, Gina N. Grantham, Susan Halabi, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2023)

546 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with BTC with ERBB2/3 amp, oe, or mut treated with P+T are reported. Methods: Eligible pts had advanced BTC, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was done in CLIA-certified, CAP-accredited labs. Dosing of P was 840 mg IV over 60 minutes (m), then 420 mg IV over 30-60 m Q3 weeks (wks); T was 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m Q3 wks until disease progression. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) at 16+ wks (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, cohort is closed for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from start of tx to PD. Results: 29 pts with BTC (15 gallbladder (GB), 11 biliary duct (BD), 3 ampulla of Vater) and ERBB2/3 amp, oe, or mut were enrolled from Feb 2017 to Jan 2022. Median (med) age was 66 years (yrs) (range, 34-83 yrs). 66% of pts were female; 52% were White, 21% were Black/African American, 10% were Asian/Asian American; 83% were not Hispanic or Latino. 83% of pts had ECOG PS 0-1 and 48% had ≥3 prior systemic regimens. 1 pt was not evaluable and excluded from efficacy analysis. The table shows efficacy outcomes. 1 pt had CR (GB; ERBB2 amp; DOR: 71.1 wks), 8 pts had PR (6 GB/2 BD; 5 ERBB2 amp; 2 ERBB2 mut; 1 ERBB3 mut/ ERBB2 amp; med DOR: 30.4 wks (4.4 to 68.9 wks)) and 2 pts had SD16+. 4 pts with a KRAS mut did not achieve OR or SD16+. 4 pts had a Grade 3 drug-related adverse or serious adverse event (SAE): anemia, diarrhea, infusion related reaction (SAE), and fatigue. Conclusions: P+T demonstrated antitumor activity in pts with advanced BTC with ERBB2/3 alterations. These data, along with results previously reported by other studies, support continued study of P+T in pts with ERBB2 amplified BTC tumors. Clinical trial information: NCT02693535 . [Table: see text]
Efficacy and tolerability of immune checkpoint inhibitors in elderly patients with MSI/dMMR gastrointestinal cancers and impact of toxicities on efficacy: The immunoMSI cohort.
Authors: Leah Mailly-Giacchetti, Raphael Colle, Daniel Lopez-Trabada Ataz, Alex Duval, Thierry Andre, Romain Cohen
Journal: Journal of Clinical Oncology (2023)

795 Background: Immune checkpoint inhibitors (ICI) are the new standard of care for some MSI/dMMR advanced tumors in first-line setting or after progression under conventional chemotherapy. Frequency of MSI/dMMR increasing with age, the tolerability and efficacy of ICIs in elderly patients, appears as a crucial clinical issue. We aimed to evaluate the tolerability and efficacy of ICIs in ≥ 75 years patients with metastatic MSI/dMMR gastro-intestinal (GI) cancer. Methods: All pts with MSI/dMMR metastatic GI cancer treated by anti-PD1 ± anti-CTLA4 without concomitant chemotherapy at Saint-Antoine hospital and included in our prospective, monocenter cohort, were analyzed. Pts were divided into the elderly (≥75 years) and non-elderly (&lt;75 years) groups. The incidence and evolution of grade ≥ 3 immune-related adverse events (irAE) and grade ≥ 2 endocrine adverse events were evaluated. Secondary objectives were progression-free survival (PFS) and overall survival (OS) regarding age and the occurrence of irAEs. Results: Two hundred and one patients were included: 24 pts≥75 years (75 to 90 years) and 177 pts&lt; 75 years (22 to 74 years). 171 (79%) had mCRC. In the entire population, the incidence of irAEs was 40.5% with anti-PD1 plus anti-CTLA4 and 23% with anti-PD1 monotherapy (p= 0.011). Combination of anti-PD1 and anti-CTLA4 were administered to 29% of the elderly group and 40% of the non-elderly group. There was no statistical difference in the incidence of irAEs between the two populations (37.5% in the elderly group vs 29% in the non-elderly group; p=0.48) neither in their type (12% vs 7% of hepatic cytolysis, 13% vs 16% of endocrine irAEs) or management (17% vs 19% corticosteroid therapy, 21% and 16% of ICI discontinuation). No significant difference was observed between elderly/non elderly for PFS (HR 0.91, 95%CI 0.40-2.06; p=0.83) and OS (HR 1.6, 95%CI 0.65-3.96; p= 0.21). Pts experiencing irAEs had superior survival outcomes than those without irAEs (PFS HR 2.93, 95%CI 1.69-5.09; p=0.02 and OS HR 2.05, 95%CI 1.13-3.74; p=0.045) in the whole cohort (n=201). Conclusions: Tolerability and efficacy of ICIs for pts with MSI/dMMR GI cancers are similar for elderly compare as for non-elderly pts. Pts experiencing irAEs had superior survival outcomes. Further prospective studies with systematic geriatric assessment are required to evaluate the tolerability of ICIs especially for frail elderly pts.
Negative hyperselection of patients with RAS wild-type metastatic colorectal cancer for panitumumab: A biomarker study of the phase III PARADIGM trial.
Authors: Kohei Shitara, Kei Muro, Jun Watanabe, Kentaro Yamazaki, Hisatsugu Ohori, Manabu Shiozawa, Hirofumi Yasui, Eiji Oki, Takeo Sato, Takeshi Naito, Yoshito Komatsu, Takeshi Kato, Junpei Soeda, Kouji Yamamoto, Riu Yamashita, Kiwamu Akagi, Atsushi Ochiai, Hiroyuki Uetake, Katsuya Tsuchihara, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2023)

11 Background: The PARADIGM trial showed longer median overall survival (OS) with first-line mFOLFOX6 plus panitumumab (PAN) vs bevacizumab (BEV) in patients (pts) with RAS wild type (WT) and left-sided metastatic colorectal cancer (mCRC) (37.9 vs 34.3 months, respectively; hazard ratio [HR], 0.82; P=0.031) and similar OS in right-sided pts (HR 1.09; Yoshino T, et al. ASCO 2022 LBA1). We evaluated the usefulness of negative hyperselection by gene alterations in ctDNA related to primary resistance to anti-EGFR therapy. Methods: Baseline plasma ctDNA (&gt;10 ng/mL and &gt;10 nM DNA) from pts enrolled in the biomarker study (NCT02394834) was assessed using a custom panel (PlasmaSELECT-R 91, PGDx). Preplanned gene alterations for hyperselection included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET, or NTRK1 fusions. Results: Among 802 pts in the full analysis set, 733 (91%) had evaluable pretreatment samples for ctDNA analysis. Of these pts, 204 (28%) had at least 1 gene alteration, including KRAS/NRAS (8%), BRAF V600E (11%), PTEN (5%), EGFR (3%), HER2 (5%), MET (1%), and fusions (1%). In 529 (72%) hyperselected pts without any gene alterations, OS tended to be longer with PAN vs BEV regardless of primary sidedness; the OS HRs ranged from 0.76 to 0.82, and the median OS gains ranged from 6.6 to 8.0 months (Table). Meanwhile, OS was similar or inferior with PAN vs BEV irrespective of the primary sidedness in pts with any of these gene alterations (Table). Conclusions: Negative hyperselection using ctDNA rather than tumor sidedness may identify appropriate pts for first-line PAN over BEV. These results warrant further validation in additional cohorts. Clinical trial information: NCT02394834 . [Table: see text]